Preparation of imidazoles

ABSTRACT

The present invention relates to preparation of imidazoles which are useful as pharmaceutical and agricultural chemicals. Specifically, the present invention relates to a process for preparing imidazoles of the formula (I): ##STR1## which comprises conducting condensation among an α,α-dihaloaldehyde compound of the formula (II): ##STR2## an aldehyde compound of the formula: R 2  --CHO and aqueous ammonia.

FIELD OF THE INVENTION

The present invention relates to a novel process for preparation ofimidazoles. In more particular, the present invention relates to a novelprocess for preparation of imidazoles which involves a condensationreaction among an α,α-dihaloaldehyde compound, an aldehyde compound, andaqueous ammonia.

Derivatives of the imidazoles which are obtained by the process of thepresent invention may be used as a useful starting material inpreparations of pharmaceutical and agricultural chemicals, and so on.

THE PRIOR ART

Processes for preparing imidazoles which are useful as startingmaterials of pharmaceutical and agricultural chemicals have beendescribed in the following publications:

a) R. Weidenhagen, et al., Ber., 68 1953 (1935); ##STR3##

b) W. Longenback, et al., Ann., 585 68 (1954); ##STR4##

c) K. Bodendorf, et al., Arch. Pharm., 298 293 (1965); ##STR5##

d) M. L. Scheinbaum, et al., Tetrahedron Lett., 2205 (1971); ##STR6##

However, the processes described in the publications have variousdrawbacks. For instance, the above reactions (a) and (b) require the useof Cu(OAc)₂, which contains a heavy metal, and hydrogen sulfide, whichis a poisonous gas, and therefore, the reactions may be dangerous tolaboratory workers. The reaction (c) often requires tedious proceduresto prepare a ketoaldoxime, which is used as a starting material. In thereaction (d), nitrosonium tetrafluoroborate is expensive.

As stated above, the previously known processes have some disadvantages,and therefore, there is a demand of developing a new process forpreparing imidazoles which is free from the above disadvantages.

DESCRIPTION OF THE PRESENT INVENTION

The present invention relates to a process for preparing imidazoles,which comprises condensating an α,α-dihaloaldehyde compound, an aldehydecompound, and aqueous ammonia at room temperature or at an elevatedtemperature.

Specifically, the present invention relates to a process for preparingimidazoles of the formula (I): ##STR7## which comprises conductingcondensation among an α,α-dihaloaldehyde compound of the formula (II):##STR8## an aldehyde compound of the formula: R² --CHO and aqueousammonia; in which X is halogen and R¹ is

(1) hydrogen;

(2) alkyl group;

(3) a haloalkyl group of the formula: Y--(CH₂)_(m) -- wherein Y ischloro or bromo, and m is an integer of from 2 to 6;

(4) acyloxyalkyl group of the formula: R³ --O--(CH₂)_(n) -- wherein n isan integer of from 2 to 6, and R³ is an acyl group;

(5) a cyanoalkyl group of the formula: NC--(CH₂)_(p) -- wherein p is aninteger of from 1 to 6;

(6) a cycloalkyl group;

(7) a group of the formula: R⁴ --S--(CH₂)_(q) -- wherein R⁴ is loweralkyl or phenyl group, and q is an integer of from 1 to 5;

(8) a group of the formula: CF₃ --(CH₂)_(r) -- wherein r is an integerof from 0 to 5;

(9) a group of the formula: ##STR9## wherein s is an integer of from 1to 5; (10) an aralkyl group of the formula: ##STR10## wherein W and Zare independently hydrogen, halogen, alkyl, alkoxy, acetylamino, cyano,or nitro group, or a group: --COOR⁵ wherein R⁵ is lower alkyl group, orW and Z taken together may form alkylenedioxy group, and t is an integerof from 1 to 5; or

(11) an aryl group of the formula: ##STR11## wherein W and Z have thesame meaning as defined above;

R² has the same meaning as R¹ or R² may represent a group selected fromthe group consisting of ##STR12## wherein R⁶ is hydrogen, lower alkyl,alkoxy or phenyl, and u is an integer of from 1 to 5.

In the specification, the term "alkyl" refers to a straight or branchedC₁ -C₁₀ alkyl group or C₃ -C₆ cycloalkyl-(C₁ -C₅) alkyl such as methyl,ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, and the like alkylgroups. In the term "acyloxyalkyl group", "acyl" refers to C₂ -C₇aliphatic acyl such as acetyl, propionyl, butyryl, and C₇ -C₁₁arylcarbonyl such as benzoyl, toluoyl, and so on. "Cycloalkyl group"refers to C₃ -C₆ cycloalkyl such as cyclopropyl, cyclobutyl,cyclopentyl, and cyclohexyl. "Lower alkyl" refers to a straight orbranched C₁ -C₆ alkyl group such as methyl, ethyl, n-propyl, i-propyl,n-butyl, i-butyl, t-butyl, and so on.

The term "alkoxy" refers to C₁ -C₆ alkyloxy such as methoxy, ethoxy,propoxy, isopropoxy, butoxy, isobutoxy, tertbutoxy, pentoxy, hexyloxy,and so on. The term "halogen" refers to chlorine, bromine, iodine, orfluorine. The term "alkylenedioxy" refers to C₁ -C₄ alkylenedioxy suchas methylenedioxy, ethylenedioxy, and so on.

The above condensation reaction can be carried out in an inert organicsolvent. The inert organic solvent includes methanol, ethanol, isopropylalcohol, tetrahydrofuran, acetonitrile, N,N-dimethylformamide,dichloromethane, 1,2-dichloroethane, benzene, toluene, and so on.Alternatively, desired imidazoles can also be prepared by reacting anacetal of α,α-dihaloaldehyde compound and an aldehyde compound with anaqueous ammonia in the presence of ammonium chloride. The startingmaterial, α,α-dihaloaldehyde compound is synthesized in accordance withthe teaching in published literatures such as N. Schamp et al.,Synthesis, 455 (1975), N. Schamp et al., Bull. Soc. Chim. Belg., 89 441(1980), F. Bellesia et al., J. Chem. Research (s). 16 (1983), and R. G.Pews et al., Synth. Commun., 15 977 (1985).

The process of the present invention is free from previously-mentioneddisadvantages, and the present invention provides a simple process forthe preparation of imidazoles. In particular, the process of the presentinvention is advantageous in the preparation of 2,4-di-substitutedimidazoles. 2,4-Di-substituted imidazoles are useful as startingmaterials of medicaments, and particularly, they are expected to bestarting materials for an anti-HIV agent.

The following examples are provided to further illustrate the process ofthe present invention. Such examples are representative only, and shouldnot be construed as limiting the scope of the invention in any respect.

EXAMPLE EXAMPLE 1 4-Isopropyl-2-methylimidazole

A mixture consisting of 3.10 g of 2,2-dichloroisovaleraldehyde and 1.76g of acetaldehyde was cooled in an ice-water, and to the mixture wasadded 27 ml of concentrated aqueous ammonia, and then the resultingmixture was stirred for 66 hours at room temperature. The product wasextracted with methylene chloride, and the extract was washed withwater, and dried over anhydrous magnesium sulfate. The solvent wasevaporated to yield 2.52 g of a crude product, which was dissolved in 10ml of isopropyl alcohol. To the resulting solution was added 10 ml of asolution of 1.80 g of oxalic acid in isopropyl alcohol to precipitatecrystals. The crude crystals (3.72 g) was recrystallized frommethanol/isopropyl alcohol to yield 3.50 g of crystals (yield: 82%).

Mp: 161°-162° C.

Elementary Analysis (for C₇ H₁₂ N₂.C₂ H₂ O₄): Theory: C, 50.46; H, 6.59;N, 13.08 (%); Found: C, 50.20; H, 6.61; N, 13.29 (%).

H-NMR (CDCl₃) [for free base] δ: 7.8 (1H, br NH), 6.60 (1H, m, C₅ --H),2.89 (1H, m, J=7 Hz, CH(Me)₂), 2.37 (3H, s, C₂ --CH₃), 1.24 (6H, d, J=7Hz, CH(Me)₂).

EXAMPLE 2 2-Phenyl-4-n-propylimidazole

A mixture consisting of 1.55 g of 2,2-dichloroisovaleraldehyde, 1.27 gof benzaldehyde, and 8 ml of acetonitrile was cooled in an ice-water,and to the mixture was added 13.5 ml of concentrated aqueous ammonia,and then the resulting mixture was stirred for 66 hours at roomtemperature. The product was extracted with methylene chloride, and theextract was washed with water, dried over anhydrous magnesium sulfate,and evaporated to yield a crude product. The crude product waschromatographed using 30 g of silica gels, thereby contaminants whichwere eluted with 5% acetonitrile/methylene chloride were removed, andfractions which were eluted with 50% acetonitrile/methylene chloridewere collected. The collected fractions were evaporated to yield 1.24 gof the residue, which was recrystallized from methylene chloride/etherto yield 0.947 g of crystals (yield: 51%).

Mp: 155°-156° C.

Elementary Analysis (for C₁₂ H₁₄ N₂): Theory: C, 77.38; H, 7.58; N,15.04 (%); Found: C, 77.57; H, 7.79; N, 15.00 (%).

H-NMR (CDCl₃) δ: 7.26-7.86 (5H, m, Ph), 6.84 (1H, s, C₅ --H), 7.7 (1H,br NH), 2.58 (2H, t, J=7 Hz, CH₂ CH₂ CH₃), 1.65 (2H, m, J=7 Hz, CH₂ CH₂CH₃), 0.93 (3H, t, J=7 Hz, CH₂ CH₂ CH₃).

EXAMPLE 3 4-Benzyl-2-methylimidazole

A mixture consisting of 2.03 g of phenyl-2,2-dichloropropione aldehyde,0.88 g of acetaldehyde, and 10 ml of acetonitrile was cooled in anice-water, and to the mixture was added 13.5 ml of concentrated aqueousammonia, and then the resulting mixture was stirred for 66 hours at roomtemperature. Then, the mixture was stirred in an oil bath at 60° C. foradditional 3 hours. The solvent of acetonitrile was evaporated in vacuoto yield the oil, which was dissolved in ether, and the resultingsolution was extracted with diluted hydrochloric acid. The aqueousextract was made basic with aqueous ammonia, and then, the solution wasextracted with methylene chloride, and the extract was washed withwater, dried over anhydrous magnesium sulfate, and evaporated off. Thecrude residue was chromatographed using 30 g of alumina, therebycontaminants which were eluted with methylene chloride were removed, andfractions which were eluted with ethyl acetate were collected. Thecollected fractions were evaporated to yield 1.04 g of the residue,which was dissolved in 10 ml of isopropyl alcohol. To the solution wasadded a solution of 544 mg of oxalic acid in 5 ml of isopropyl alcoholto precipitate 1.38 g of crystals (yield: 53%).

Mp: 162°-163° C.

Elementary Analysis (for C₁₁ H₁₂ N₂.C₂ H₂ O₄): Theory: C, 59.53; H,5.38; N, 10.68 (%); Found: C, 59.28; H, 5.43; N, 10.61 (%).

H-NMR (CDCl₃) [for free base] δ: 7.14 (5H, m, Ph), 6.55 (1H, s, C₅ --H),5.53 (1H, br, NH), 3.88 (3H, s, C₂ --CH₃).

EXAMPLES 4-16

Various imidazoles were prepared according to the procedure as definedabove. Conditions of the reactions and data of the resulting compoundsare shown in the following table 1.

    TABLE 1      ##STR13##       reaction yield EA (%) .sup.1 H-NMR(CDCl.sub.3)  R.sup.1, X R.sup.2     con. A sol. temp. time (g) molecular  Found δ(J,Hz) Exa. (g) (g)     (ml) (ml) (°C.) (hr) (%) formula m.p. (°C.) (Theory) for     free base                    4 n-Pr,Cl1.55 CH.sub.30.88 13.5 none r.t. 24 1.6376     C.sub.7 H.sub.12 N.sub.2.C.sub.2 H.sub.2      O.sub.4 120-121 C.H.N. 50.26(50.46)       6.61(6.59)13.00(13.08)     ##STR14##      5 n-Pr,Cl1.55 PhCH.sub.21.44 13.5 CH.sub.3 CN8 r.t. 66 1.7259 C.sub.13     H.sub.16 N.sub.2.C.sub.2 H.sub.2 O.sub.4 158-159 C.H.N. 62.14(62.06)     6.37(6.25)9.55(9.65)      ##STR15##      6 H,Cl CH.sub. 3 13.5 none r.t. 19 0.416 C.sub.4 H.sub.6 N.sub.2     144-145   9.02(1H, br.s, NH), 6.96(2H, s, C.sub.4H and C.sub.5H)  1.31     0.88     51     2.43(3H, s, C.sub.2CH.sub.3) 7 H,Cl ph 13.5 CH.sub.3 CN     r.t. 19 0.483 C.sub.9 H.sub.8 N.sub.2 151   7.33-7.41 and 7.85-7.90(5H,     m, ph),  1.31 1.27  5   34     7.14(2H, s, C.sub.4H and C.sub.5H),     6.95(1H, br.s, NH) 8 phCH.sub.2,Cl2.03 H0.60 13.5 CH.sub.3 CN10 r.t. 67     0.90357 C.sub.10 H.sub.10 N.sub.2 81-82 C.H.N. 75.92(75.92)      6.43(6.37)17.76(17.71)      ##STR16##      9 phCH.sub.2,Cl2.03 CH.sub.3 OCH.sub.21.48 13.5 none 55 24 1.2141     C.sub.12 H.sub.14 N.sub.2 O.C.sub.2 H.sub.2 O.sub.4 91-92 C.H.N.     57.62(57.53)      5.37(5.52)9.57(9.59)     ##STR17##       10       phCH.sub.2,Cl2.03     ##STR18##      13.5 none 55 24 0.58322 C.sub.17 H.sub.16 N.sub.2 O 198-199 C.H.N.     77.38(77.24)      6.10(6.10)10.59(10.60)     ##STR19##       11       i-Pr,Cl1.55     ##STR20##      13.5 CH.sub.2 Cl.sub.210 r.t. 72 0.73033 C.sub.12 H.sub. 13 N.sub.2 Cl     192-193 C.H.N.Cl. 65.56(65.30) 5.87(5.94)12.69(12.70)16.34(16.07)      ##STR21##       12  n-Pr,Cl1.55 NCCH.sub.2 CH.sub.21.66 13.5 none r.t. 66 1.0464     C.sub.9 H.sub.13 N.sub.3 96-97 C.H.N. 66.28(66.22)      8.01(8.03)25.76(25.75)      ##STR22##        13       n-Pr,Cl1.55     ##STR23##      13.5 CH.sub.2 Cl.sub.210 r.t. 24 0.89748 C.sub.11 H.sub.13 N.sub.3     160-161 C.H.N. 70.74(70.56)      7.09(7.00)22.35(22.44)     ##STR24##       14       i-Pr,Cl1.55     ##STR25##      13.5 CH.sub.2 Cl.sub.216 r.t. 24 0.42819 C.sub.12 H.sub.13 N.sub.3     O.sub.2 181-182 C.H.N. 62.47(62.32)      5.81(5.67)18.08(18.17)     ##STR26##       15  C.sub.2 H.sub.5,Br2.30 CH.sub.30.88 13.5 CH.sub.2 Cl.sub.210 r.t.     21 1.4070 C.sub.6 H.sub.10 N.sub.2.C.sub.2 H.sub.2 O.sub.4 145-146     C.H.N. 47.90(47.99)      5.88(6.04)13.95(13.99)     ##STR27##      16  C.sub.2 H.sub.5,Br2.30 CH.sub.3 CH.sub.21.16 13.5 CH.sub.2      Cl.sub.210 r.t. 21 1.3463 C.sub.7 H.sub.12 N.sub.2.C.sub.2 H.sub.2     O.sub.4 95-96 C.H.N. 50.45(50.46)      6.61(6.59)13.05(13.08)     ##STR28##     Exa.; Example Number     con. A; concentrated aqueous ammonia     sol.; solvent     temp.; temperature     EA; Elementary Analysis

EXAMPLE 17 4-n-Butyl-imidazole ##STR29##

A mixture consisting of 1.69 g of 2,2-dichloro-n-hexyl aldehyde and 1.62g of 37% aqueous formaldehyde was cooled in an ice-water, and to themixture was added 13.5 g of concentrated aqueous ammonia, and then themixture was stirred for 22.5 hours at room temperature. The product wasextracted with methylene chloride, and the extract was washed withwater, dried over anhydrous magnesium sulfate, and evaporated to yield1.26 g of a crude product, which was dissolved in 5 ml of isopropylalcohol. To the solution was added 5 ml of a solution of 0.90 g ofoxalic acid in isopropyl alcohol to precipitate crystals. The crudecrystals (1.49 g) were recrystallized from methanol/isopropyl alcohol toyield 1.39 g of the oxalate (mp: 182°-184° C.).

A solution of the oxalate dissolved in water was made basic with aqueoussodium bicarbonate, and the solution was extracted with methylenechloride, washed with water, dried over anhydrous potassium carbonate,and evaporated to yield 0.907 g of the title compound as white crystals(yield: 73.0%).

Mp: 42°-45° C.

¹ H-NMR (CDCl₃) δ: 7.99 (1H, br, NH), 7.55 (1H, s, C₂ --H), 6.78 (1H, s,C₅ --H) 2.61 (2H, t, J=8 Hz, --CH₂ --), 1.37 and 1.63 (4H, m, --CH₂ --),0.92 (3H, t, J=7 Hz, CH₃).

What is claimed is:
 1. A process for preparing imidazoles of the formula(I): ##STR30## in which R¹ is (1) hydrogen; (2) alkyl group; (3) ahaloalkyl group of the formula: Y--(CH₂)_(m) -- wherein Y is chloro orbromo, and m is an integer of from 2 to 6; (4) an acyloxyalkyl group ofthe formula: R³ --O--(CH₂)_(n) -- wherein n is an integer of from 2 to6, and R³ is an acyl group; (5) a cyanoalkyl group of the formula:NC--(CH₂)_(p) -- wherein p is an integer of from 1 to 6; (6) acycloalkyl group; (7) a group of the formula: R⁴ --S--(CH₂)_(q) --wherein R⁴ is lower alkyl or phenyl group, and q is an integer of from 1to 5; (8) a group of the formula: CF₃ --(CH₂)_(r) -- wherein r is aninteger of from 0 to 5; (9) a group of the formula: ##STR31## wherein sis an integer of from 1 to 5; (10) an aralkyl group of the formula:##STR32## wherein W and Z are independently hydrogen, halogen, alkyl,alkoxy, acetylamino, cyano, or nitro group, or a group: --COOR⁵ whereinR⁵ is lower alkyl, or W and Z, taken together, may form alkylenedioxygroup, and t is an integer of from 1 to 5; or (11) an aryl group of theformula: ##STR33## wherein W and Z have the same meaning as definedabove;R² has the same meaning as R¹ or R² may represent a group selectedfrom the group consisting of ##STR34## wherein R⁶ is hydrogen, loweralkyl, alkoxy, or phenyl, and u is an integer of from 1 to 5,whichcomprises conducting condensation among an α,α-dihaloaldehyde compoundof the formula (II): ##STR35## in which R1 is as defined above, and X ishalogen, an aldehyde compound of the formula: R² --CHO in which R² is asdefined above, and aqueous ammonia.
 2. The process of claim 1, in whichR¹ and R² are independently alkyl group.
 3. The process of claim 2, inwhich R¹ and R² are independently methyl, ethyl, or propyl.
 4. Theprocess of claim 1, in which R¹ is alkyl group and R² is hydrogen.